HIV-1 protease is the target of the most effective anti-viral drugs for the treatment of HIV-1 infection. All these drugs derive from successful structure-based design studies. The enzyme cleaves the viral gag-pol polyprotein at least ten unique sites and is essential for maturation of the virion and thus the spread of the virus. Therefore, it has been a prime target for drug design research. Unfortunately the medical efficacy of the current drugs is proving to be short lived, as viable mutant variants of HIV-1 protease confer drug resistance. Drug resistance is a subtle change in the balance of recognition events, between the relative affinity of the enzyme to bind inhibitors and its ability to bind and cleave substrates. Since HIV-1 protease binds substrates and inhibitors at the same active site, a change that alters inhibitor binding also alters substrate binding. We previously developed a structural rationale that explains how HIV protease recognizes its substrates and how drug resistant mutations occur within the active site of HIV protease, while still maintaining substrate recognition. HIV protease recognizes a conserved asymmetric shape that the substrates adopt. This shape is not discernable from the substrate's amino acid sequence, but only from their complexed three-dimensional structures. We defined this shape, or consensus volume, as the substrate envelope". This led us to the realization that most active-site drug-resistant mutations within HIV protease occur where the inhibitors protrude beyond the consensus substrate envelope and contact the protease. Those protease residues are prime positions for drug resistance to occur, as they are more important for inhibitor binding than for substrate binding. In this proposal we elucidate the interdepence of substrate recognition and hypothesize that drug-induced co-evolution of HIV-1 protease and its polyprotein substrates occurs when the substrates extend beyond the consensus "substrate envelope" and that co- evolution occurs in an interdependent manner.